Dietary Phytoestrogen Intake and Risk of Receptor-Defined Breast Cancer Subtypes: A Prospective Analysis of the PLCO Cancer Screening Trial Cohort

Background: Phytoestrogens may influence breast carcinogenesis through hormone-related and nonhormone–mediated mechanisms, yet prospective evidence by receptor-defined subtype in US populations remains limited. We evaluated associations between dietary phytoestrogen intake and the risk of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2)–defined breast cancer. Methods: We analyzed 51,530 postmenopausal women in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Baseline intake of total and individual phytoestrogens was assessed using a validated food frequency questionnaire. Incident breast cancers were classified by ER, PR, and HER2 status. Cause-specific Cox proportional hazards models estimated hazard ratios (HR) and 95% confidence intervals (CI) across tertiles of intake, adjusting for established breast cancer risk factors. Results: During follow-up, 2,364 incident breast cancers were identified. Higher coumestrol intake was associated with a lower hazard of ER– breast cancer (tertile 3 vs. tertile 1: HR, 0.67; 95% CI, 0.50-0.91; P trend = 0.014) and PR– breast cancer (HR, 0.74; 95% CI, 0.59-0.93; P trend = 0.013). Higher total isoflavone intake was associated with a lower hazard of HER2+ disease (HR, 0.62; 95% CI, 0.45-0.87; P trend = 0.005), with similar findings for daidzein. No significant associations were observed for ER+ or PR+ tumors. Conclusions: Associations between phytoestrogen intake and breast cancer differed by receptor-defined subtype, with inverse associations observed primarily for receptor-negative and HER2+ tumors. Impact: These findings suggest that associations between dietary phytoestrogen intake and breast cancer may vary across receptor-defined subtypes and highlight the need for replication using biomarker-based measures and populations with higher exposure levels.